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However, variants at these loci are largely noncoding, making it difficult to assess their function and whether they are causal. Here, we present a single-cell gene expression and chromatin accessibility atlas of human retinal pigment epithelium (RPE) and choroid to systematically analyze both coding and noncoding variants implicated in AMD. We employ HiChIP and Activity-by-Contact modeling to map enhancers in these tissues and predict cell and gene targets of risk variants. We further perform allele-specific self-transcribing active regulatory region sequencing (STARR-seq) to functionally test variant activity in RPE cells, including in the context of complement activation. Our work nominates new pathogenic variants and mechanisms in AMD and offers a rich and accessible resource for studying diseases of the RPE and choroid.<\/jats:p>","DOI":"10.1101\/2025.03.21.644670","type":"posted-content","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T03:53:17Z","timestamp":1742961197000},"source":"Crossref","is-referenced-by-count":3,"title":["Single-cell multiome and enhancer connectome of human retinal pigment epithelium and choroid nominate pathogenic variants in age-related macular degeneration"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1557-8510","authenticated-orcid":false,"given":"Sean K.","family":"Wang","sequence":"first","affiliation":[{"name":"Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA"},{"name":"Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA"},{"name":"Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surag","family":"Nair","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Stanford University, Stanford, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reshma","family":"Korasaju","sequence":"additional","affiliation":[{"name":"Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yun","family":"Chen","sequence":"additional","affiliation":[{"name":"Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anshul","family":"Kundaje","sequence":"additional","affiliation":[{"name":"Department of Computer Science, Stanford University, Stanford, CA, USA"},{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuwen","family":"Liu","sequence":"additional","affiliation":[{"name":"Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China"},{"name":"Kunpeng Institute of Modern Agriculture at Foshan, Chinese Academy of Agricultural Sciences, Foshan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ningli","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China"},{"name":"Henan Academy of Innovations in Medical Science, Henan, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Howard Y.","family":"Chang","sequence":"additional","affiliation":[{"name":"Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA"},{"name":"Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041200493548000_2025.03.21.644670v1.1","doi-asserted-by":"crossref","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis","volume":"2","year":"2014","journal-title":"Lancet. 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